地高辛抗血清对老龄大鼠心肌缺氧复氧损伤影响的体外实验

目的:观察内洋地黄素水平在老龄大鼠心肌细胞缺氧复氧损伤中的变化以及地高辛抗血清的保护作用。方法:实验于2005-04/05在皖南医学院病理生理教研室完成。取10只24月龄和10只6月龄雄性普通级SD大鼠,分别制备青年和老龄大鼠心肌细胞匀浆,老龄和成年大鼠为两大组,每组分为7小组,即每只大鼠心肌随机分到各小组中,共计14小组,每组10支试管。正常对照组:给予CO2和O2的混合气体(1∶19)通气40min;缺氧复氧组:CO2,O2,N2混合气体(5∶4∶91)通气20min后换成CO2和O2的混合气体(1∶19)通气20min;阴性对照组:同缺氧复氧组,但于再给氧前加入0.1mL的非特异性灭活兔血清;地高辛抗血清组:同缺氧复氧组,但于再给氧前加入0.1mL的非特异性地高辛抗血清(分别为1∶90000,60000,30000,10000)。观察大鼠心肌细胞钠-钾-三磷酸腺苷酶活性和线粒体内钙聚集程度,分析其剂量-效应关系。结果:①缺氧复氧时,青年组和老龄组大鼠心肌分泌内洋地黄素均显著升高,但老龄组显著低于青年组[(0.081±0.03),(0.153±0.06);(0.074±0.04),(0.125±0.05)ng/g;P<0.05]。②缺氧复氧时,老龄组与青年组心肌细胞钠-钾-三磷酸腺苷酶活性显著受抑制[(0.239±0.015),(0.778±0.050);(0.350±0.047),(0.836±0.044)μkat/g;P<0.05],老龄组与青年组相比,其抑制效应显著增强(P<0.05)。③缺氧复氧时,老龄组线粒体内钙与青年组比较明显增强[(0.082±0.011),(0.495±0.095);(0.075±0.008),(0.412±0.084)mmol/L,P<0.05]。④老龄组和青年组相比,地高辛抗血清呈剂量依赖性的恢复钠-钾-三磷酸腺苷酶活性(r=0.695,0.797,n=5,P<0.05),减轻线粒体内钙聚集(r=-0.565,-0.649,n=5,P<0.05);经直线回归分析发现,老龄鼠回归系数大于青年组(酶活性抑制K=1.50,0.94,线粒体内钙K=-7.43,-6.46)。结论:心肌细胞缺氧复氧时,老龄鼠损伤较青年大鼠更显著,其机制与老龄大鼠心肌细胞钠-钾-三磷酸腺苷酶对内洋地黄素敏感性增加有关,地高辛抗血清对老龄大鼠心肌细胞缺氧复氧保护作用更有效。     

Inosine monophosphate dehydrogenase and myeloid cell maturation

In previous studies of purine ribonucleotide metabolism in the human myeloid leukemia cell line HL-60, we observed that there is a down- regulation of guanine ribonucleotide biosynthesis from the central intermediate, inosine monophosphate (IMP) and a depletion of intracellular guanosine triphosphate (GTP) and guanosine diphosphate (GDP) pools that occur during the induced maturation of these cells. We also found that inhibitors of IMP dehydrogenase, the enzyme that catalyzes the first step of guanylate synthesis from IMP, are potent inducers of HL-60 maturation. Because of these observations we specifically investigated the activity of IMP dehydrogenase in HL-60 cells and in a new inducible human myeloid leukemia cell line, RDFD2- 25, both during maintenance culture and during induced maturation of the cells. Enzyme activity was examined directly in cell extracts with a radiometric assay that measures free 3H2O formed from [2-3H] IMP during the conversion of IMP to XMP. Uninduced HL-60 and RDFD2 cells in maintenance culture were found to have high levels of IMPD activity (5.2 to 5.7 pmol IMP metabolized/10(7) cells/min) compared with normal neutrophils and monocytes that had been purified from blood (less than 1.5 pmol IMP metabolized/10(7) cells/min). However, when HL-60 and RDFD2-25 cells were induced to mature with retinoic acid (10(-6) mol/L), dimethylformamide (6 X 10(-2) mol/L), or a known IMPD inhibitor, tiazofurin (10(-6) mol/L), IMPD activity in the cells fell by 51% to 80% within three to six hours. These changes in IMPD activity preceded detectable functional and antigenic maturation of the cells by at least 12 hours and were not temporally related to changes in cellular proliferation. These findings are consistent with the concept that the regulation of myeloid cell maturation may be influenced by intracellular concentrations of guanine ribonucleotides because IMP dehydrogenase activity is known to be rate limiting for the production of these nucleotides.     

Hematopoietic and fatty bone marrow distribution in the normal and ischemic hip: new observations with 1.5-T MR imaging

The conversion of hematopoietic to fatty marrow is known to correlate with physiologic decreases in intramedullary blood flow. To determine whether the chronology of conversion is altered in patients with hip ischemia, T1-weighted magnetic resonance (MR) images of the hips in 50 healthy people and 27 with documented avascular necrosis (AVN) were reviewed. The distribution of fatty (high-signal) versus hematopoietic (low-signal) marrow was noted with respect to age. All patients had fatty marrow in the femoral capital epiphysis and greater trochanter. Hematopoietic intertrochanteric marrow was seen in 95% (80 of 84) of femurs in control subjects less than 50 years old, but in only 12.5% (two of 16) of those in control subjects older than 50 years (P less than .005). Only 33% (19 of 57) of patients less than 50 years with AVN had predominantly hematopoietic intertrochanteric marrow (P less than .005). The early conversion to fatty marrow in most patients with AVN as depicted by MR imaging may be an effect of decreased vascularity of the proximal femur and may allow the identification of patients at increased risk for AVN.     

Young age at first pregnancy does protect against early onset breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation carriers

Purpose

Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.

Methods

Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan–Meier analyses were performed.

Results

2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30–39 years. Kaplan–Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).

Conclusions

The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

     

Femoral head avascular necrosis: correlation of MR imaging, radiographic staging, radionuclide imaging, and clinical findings

To better correlate the appearance of avascular necrosis (AVN) of the femoral head on magnetic resonance (MR) images with the stage of disease, MR images of 56 proved AVN lesions were compared with staging from corresponding radiographs (n = 56), Tc-99m scans (n = 41), and grade of symptoms (n = 28). Fractures complicating AVN were seen in 28 (50%) of 56 radiographs (radiographic stages III-V). With long repetition (TR) and echo delay (TE) times, a characteristic "double line sign" consisting of high signal intensity inside a low-intensity peripheral rim was seen in 45 lesions (80%). The central region within the rim was isointense with marrow fat on both short and long TR and TE images in 20 (71%) of 28 lesions uncomplicated by fracture (stages I-II) but in only four (14%) of 28 stage III-V lesions (P less than .001). Symptoms were least severe in lesions isointense with fat and most severe in lesions with low-signal central regions at short and long TRs and TEs. The peripheral double line sign on long TR/TE images may add specificity to the diagnosis of AVN by MR imaging. A chronologic pattern of central MR signal features is presented which may allow staging of AVN by MR imaging.